Oligonephronia: another piece in the CKDu jigsaw?

Rates of chronic kidney disease of unknown etiology are high in Aguascalientes, Mexico. Kidneys of adolescents are small by ultrasonography, compatible with oligonephronia, whereas proteinuria and higher estimated glomerular filtration rates and blood pressures among those with relatively higher kidney volumes probably flag relatively greater degrees of compensatory hypertrophy. Glomerulomegaly and podocytopathy, and later segmental glomerulosclerosis in biopsies, suggest a cascade driven by nephron deficiency. Better measures of glomerular number and volume should improve understanding, facilitate risk assessment, and guide interventions.

Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.

Pharmacogenomic analysis of a genetically distinct Indigenous population.

Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.

The genomic landscape of blood groups in Indigenous Australians in remote communities.

BACKGROUND: Red blood cell (RBC) membrane-associated blood group systems are clinically significant. Alloimmunisation is a persistent risk associated with blood transfusion owing to the antigen polymorphisms among these RBC-associated blood groups. Next-generation sequencing (NGS) offers an opportunity to characterize the blood group variant profile of a given individual. Australia comprises a large multiethnic population where most blood donors are Caucasian and blood group variants remain poorly studied among Indigenous Australians. In this study, we focused on the Tiwi Islanders, who have lived in relative isolation for thousands of years. METHODS AND MATERIALS: We predicted the blood group phenotype profiles in the Tiwi (457) and 1000 Genomes Phase 3 (1KGP3-2504) cohort individuals using RBCeq (https://www.rbceq.org/). The predicted phenotype prevalence was compared with the previous literature report. RESULTS: We report, for the first time, comprehensive blood group profiles corresponding to the 35 known blood group systems among the Indigenous Tiwi islander population and identify possible novel antigen variants therein. Our results demonstrate that the genetic makeup of the Tiwi participants is distinct from that of other populations, with a low prevalence of LU (Au[a-b+]) and ABO (A2) and D+C+c+E+e- phenotype, an absence of Diego blood group variants, and a unique RHD (DIII type4) variant. CONCLUSION: Our results may contribute to the development of a database of predicted phenotype donors among the Tiwi population and aid in improving transfusion safety for the ~2800 Tiwi people and the ~800,000 other Indigenous Australians throughout the nation.

Determining the association between the type of intervention for ischaemic heart disease and mortality and morbidity in patients with chronic kidney disease.

BACKGROUND: Association between chronic kidney disease (CKD) and ischaemic heart disease (IHD) is well known. Clinically, because of the use of intra-arterial contrast, coronary angiograms are sometimes not performed to avoid further deterioration in kidney function among CKD patients. AIMS: To identify whether intervention for non-ST elevation myocardial infarction (NSTEMI) is associated with increased mortality or further renal deterioration. METHODS: A retrospective observational cohort study involving 144 patients with a diagnosis of IHD in the CKD.QLD registry from May 2011 to August 2017, with a minimum of 2-years follow up, was undertaken. Patients were divided into two groups based on whether they obtained an interventional or medical management for NSTEMI. RESULTS: Fifty-nine patients had medically managed and 85 patients had intervention for IHD. Patients in the medically managed group were observed to be significantly older (median: 78 vs 69 years; P < 0.05) with worse baseline renal function (median: 31 vs 36 mL/min/1.73 m2 ; P <0.05) and higher serum urate level (median: 0.5 vs 0.4 mmol/L; P = 0.2). The interventional group had lower prevalence of diabetes, dyslipidaemia, cerebrovascular disease and peripheral vascular disease. Although this was not significant, Kaplan-Meier analysis revealed a significant decrease in mean survival of medically managed group compared with the interventional group. Furthermore, post adjustment for age and above comorbidities, the medically managed group and higher age were associated with significantly higher mortality. However, the patients in the medically managed and interventional groups had no significant difference in delta estimated glomerular filtration rate. CONCLUSIONS: In this observational study, intervention for IHD was associated with increased survival with no change in renal disease progression in comparison with medically managed patients.

Chronic kidney disease in public renal practices in Queensland, Australia, 2011-2018.

AIM: To describe adults with (non-dialysis) chronic kidney disease (CKD) in nine public renal practice sites in the Australian state of Queensland. METHODS: 7,060 persons were recruited to a CKD Registry in May 2011 and until start of kidney replacement therapy (KRT), death without KRT or June 2018, for a median period of 3.4 years. RESULTS: The cohort comprised 7,060 persons, 52% males, with a median age of 68 yr; 85% had CKD stages 3A to 5, 45.4% were diabetic, 24.6% had diabetic nephropathy, and 51.7% were obese. Younger persons mostly had glomerulonephritis or genetic renal disease, while older persons mostly had diabetic nephropathy, renovascular disease and multiple diagnoses. Proportions of specific renal diagnoses varied >2-fold across sites. Over the first year, eGFR fell in 24% but was stable or improved in 76%. Over follow up, 10% started KRT, at a median age of 62 yr, most with CKD stages 4 and 5 at consent, while 18.8% died without KRT, at a median age of 80 yr. Indigenous people were younger at consent and more often had diabetes and diabetic kidney disease and had higher incidence rates of KRT. CONCLUSION: The spectrum of characteristics in CKD patients in renal practices is much broader than represented by the minority who ultimately start KRT. Variation in CKD by causes, age, site and Indigenous status, the prevalence of obesity, relative stability of kidney function in many persons over the short term, and differences between those who KRT and die without KRT are all important to explore.

The prevalence of Fabry disease in a statewide chronic kidney disease cohort - Outcomes of the aCQuiRE (Ckd.Qld fabRy Epidemiology) study.

BACKGROUND: Prevalence of Fabry disease amongst Chronic Kidney Disease (CKD) patients on haemodialysis has been shown to be approximately 0.2%. METHODS: We undertook a cross-sectional study employing a cascade screening strategy for Fabry Disease amongst 3000 adult, male and female patients affected by CKD stage 1-5D/T at public, specialty renal practices within participating Queensland Hospital and Health Services from October 2017 to August 2019. A multi-tiered FD screening strategy, utilising a combination of dried blood spot (DBS) enzymatic testing, and if low, then lyso-GB3 testing and DNA sequencing, was used. RESULTS: Mean (SD) age was 64.0 (15.8) years (n = 2992), and 57.9% were male. Eight participants withrew out of the 3000 who consented. Of 2992 screened, 6 (0.20%) received a diagnosis of FD, 2902 (96.99%) did not have FD, and 84 (2.81%) received inconclusive results. Of the patients diagnosed with FD, mean age was 48.5 years; 5 were male (0.29%) and 1 was female (0.08%); 4 were on kidney replacement therapy (2 dialysis and 2 transplant); 3 were new diagnoses. CONCLUSIONS: Estimated overall FD prevalence was 0.20%. Screening of the broader CKD population may be beneficial in identifying cases of FD. TRIAL REGISTRATION: The aCQuiRE Study has been prospectively registered with the Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au ) as pj09946 (Registered 3rd July 2017).

Podocyte endowment and the impact of adult body size on kidney health.

Low birth weight is a risk factor for chronic kidney disease, whereas adult podocyte depletion is a key event in the pathogenesis of glomerulosclerosis. However, whether low birth weight due to poor maternal nutrition is associated with low podocyte endowment and glomerulosclerosis in later life is not known. Female Sprague-Dawley rats were fed a normal-protein diet (NPD; 20%) or low-protein diet (LPD; 8%), to induce low birth weight, from 3 wk before mating until postnatal day 21 (PN21), when kidneys from some male offspring were taken for quantitation of podocyte number and density in whole glomeruli using immunolabeling, tissue clearing, and confocal microscopy. The remaining offspring were fed a normal- or high-fat diet until 6 mo to induce catch-up growth and excessive weight gain, respectively. At PN21, podocyte number per glomerulus was 15% lower in low birth weight (LPD) than normal birth weight (NPD) offspring, with this deficit greater in outer glomeruli. Surprisingly, podocyte number in LPD offspring increased in outer glomeruli between PN21 and 6 mo, although an overall 9% podocyte deficit persisted. Postnatal fat feeding to LPD offspring did not alter podometric indexes or result in glomerular pathology at 6 mo, whereas fat feeding in NPD offspring was associated with far greater body and fat mass as well as podocyte loss, reduced podocyte density, albuminuria, and glomerulosclerosis. This is the first report that maternal diet can influence podocyte endowment. Our findings provide new insights into the impact of low birth weight, podocyte endowment, and postnatal weight on podometrics and kidney health in adulthood.NEW & NOTEWORTHY The present study shows, for the first time, that low birth weight as a result of maternal nutrition is associated with low podocyte endowment. However, a mild podocyte deficit at birth did not result in glomerular pathology in adulthood. In contrast, postnatal podocyte loss in combination with excessive body weight led to albuminuria and glomerulosclerosis. Taken together, these findings provide new insights into the associations between birth weight, podocyte indexes, postnatal weight, and glomerular pathology.

Heterogeneity in patterns of progression of chronic kidney disease.

BACKGROUND: Progression of kidney disease is a deceptively simple word for a complex bio-clinical process, evidenced by the number of definitions in the literature. This has led to confusion and differences in interpretation of studies. METHODS: We describe different patterns of progression, the performance of different definitions of progression and factors associated with chronic kidney disease (CKD) progression in a public renal service in Australia, in a study of patients enrolled in the CKD.QLD Registry with a minimum of 2 years' follow up. RESULTS: Nine patterns of changing estimated glomerular filtration rate (eGFR) over two consecutive 12-month periods were identified. Most common was a stable eGFR over 2 years (30%), and the least was a sustainable improvement of eGFR over both periods (2.1%). There was a lack of congruence between the several definitions of progression of CKD evaluated. More people progressed using the definition of decline of eGFR of >5 mL/min/1.73 m2 /year (year 1 = 30.2%, year 2 = 20.7%) and the least using development of end-stage renal disease (year 1 = 5.4%, year 2 = 9.9%). Age (40-59, ≥80 years), degree of proteinuria at baseline (nephrotic range) and CKD aetiology (renal vascular disease, diabetic nephropathy) were significantly associated with eGFR decline over 2 years. CONCLUSIONS: This is one of the first demonstrations of the great variations among and within individuals in the progression of CKD over even a period as short as 2 years. Findings suggest considerable potential for renal function recovery and stability while demonstrating the importance of using identical definitions for comparisons across datasets from different sources.

Oral health of aboriginal people with kidney disease living in Central Australia.

BACKGROUND: Associations between kidney disease and periodontal disease are not well documented among Aboriginal people of Australia. The purpose of this investigation was to report and compare demographic, oral health, anthropometric and systemic health status of Aboriginal Australians with kidney disease and to compare against relevant Aboriginal Australians and Australian population estimates. This provides much needed evidence to inform dental health service provision policies for Aboriginal Australians with kidney disease. METHODS: Sample frequencies and means were assessed in adults represented in six datasets including: (1) 102 Aboriginal Australians with kidney disease residing in Central Australia who participated in a detailed oral health assessment; (2) 312 Aboriginal participants of the Northern Territory's PerioCardio study; (3) weighted estimates from 4775 participants from Australia's National Survey of Adult Oral Health (NSAOH); (4) Australian 2016 Census (all Australians); (5) National Health Survey 2017-2018 (all Australians) and; (6) Australian Health Survey: Biomedical Results for Chronic Diseases, 2011-2012 (all Australians). Oral health status was described by periodontal disease and experience of dental caries (tooth decay). Statistically significant differences were determined via non-overlapping 95% confidence intervals. RESULTS: Aboriginal Australians with kidney disease were significantly older, less likely to have a tertiary qualification or be employed compared with both PerioCardio study counterparts and NSAOH participants. Severe periodontitis was found in 54.3% of Aboriginal Australians with kidney disease, almost 20 times the 2.8% reported in NSAOH. A higher proportion of Aboriginal Australians with kidney disease had teeth with untreated caries and fewer dental restorations when compared to NSAOH participants. The extent of periodontal attachment loss and periodontal pocketing among Aboriginal Australians with kidney disease (51.0%, 21.4% respectively) was several magnitudes greater than PerioCardio study (22.0%, 12.3% respectively) and NSAOH (5.4%, 1.3% respectively) estimates. CONCLUSIONS: Aboriginal Australians with kidney disease exhibited more indicators of poorer oral health than both the general Australian population and a general Aboriginal population from Australia's Northern Territory. It is imperative that management of oral health among Aboriginal Australians with kidney disease be included as part of their ongoing medical care.

Five enablers to deliver safe water and effective sewage treatment to remote Indigenous communities in Australia.

CONTEXT: Safe drinking water and effective sanitation in remotely located Indigenous communities are essential services and their provision is a human right. Yet sustainable provision of these services can be challenging. Risks to human health from inadequate provision include transmission of hygiene-related infections from microbial contamination, and toxic chemicals that may cause kidney damage or dysfunction. This narrative review is conducted in the current context of the United Nations Sustainable Development Goal 6, the 'refresh' of the National Agreement on Closing the Gap in Indigenous inequity, and the 2020 Inquiry of the Australian Productivity Commission into the National Water Reform. ISSUES: Challenges to providing drinking water supplies in remote communities include biological contamination and chemical contamination from naturally occurring elements in groundwater. Monitoring regimes can be challenged by remote location, minimal and/or high turnover of staff and a lack of ongoing maintenance. Unpalatable water can shift consumption to purchased drinks such as sugar-sweetened beverages, with flow-on health impacts of diet-related chronic conditions such as overweight and obesity, and type 2 diabetes. LESSONS LEARNED: By analysing two effective programs from remote areas of New South Wales and the Torres Strait Islands in Queensland, Australia, five enablers were identified: people factors (support, training, cultural competence); cross-agency collaboration (regulators, funders, state and local government); technology that is fit for place, purpose and local people; funding that is sufficient and sustainable; and taking a systems view of water and sanitation.

An update on chronic kidney disease in Aboriginal Australians.

We provide a brief update on some aspects of chronic kidney disease (CKD) in Indigenous Australians, with CKD referring to all stages of pre-terminal kidney disease, as well as to end-stage kidney failure (ESKF), whether or not a person receives renal replacement therapy (RRT). Recently recorded rates of ESKF and RRT were 6- and 8-fold those recoded for non-Indigenous Australians with age adjustment, while non-dialysis CKD hospitalizations and CKD-attributed deaths were 8-fold and 3-fold higher. The median age of Indigenous people who developed ESKF was ~ 30 years less than for non-Indigenous people, and 84% of them received RTT, while only half of non-Indigenous people with ESKF did so. However, the nationwide average Indigenous incidence rate of RRT appears to have stabilized. The 2012 Australian Health Survey showed elevated levels of CKD markers in Indigenous people at the community level. For all CKD parameters, rates among Indigenous people were strikingly correlated with increasing remoteness of residence and socioeconomic disadvantage, and there was a female predominance in remote areas. The burden of renal disease in Australian Indigenous people is seriously understated by Global Burden of Disease Mortality methodology, because it employs underlying cause of death only, and because deaths of people on RRT are frequently attributed to non-renal causes. These data give a much-expanded view of CKD in Aboriginal people. Methodologic approaches must be remedied for a full appreciation of the burden, costs, and outcomes of the disease, to direct appropriate policy development.

Impact of cardiovascular events on mortality and progression of renal dysfunction in a Queensland CKD cohort.

AIM: Cardiovascular events (CVE) are common co-morbidities amongst patients with chronic kidney disease (CKD). The impact of CVE on the subsequent pattern and rate of deterioration of kidney function is not well described. METHODS: A retrospective cohort study of 1123 Royal Brisbane and Women's Hospital patients enrolled in the CKD.QLD registry from May 2011 to August 2017 was undertaken. Participants CVE data and renal function (eGFR CKD-EPI) were extracted from clinical records. Participants who ultimately started kidney replacement therapy (KRT) were imputed an eGFR of 8 mL/min/1.73 m2 at the date of the first KRT treatment. Annualized percentage delta eGFR was used to explore the association between CVE and rate of renal deterioration. Mortality was ascertained through electronic health records. RESULTS: There were 235 CVE events amongst 222 participants over a period of 6 years. One hundred and forty-four participants experienced ischaemic heart disease (IHD), 51 participants had stroke, 40 participants had peripheral vascular disease (PVD) and 13 participants had more than one event. CVE were associated with significantly shorter time to death in participants who experienced one CVE compared with those without a CVE (1901.2 days vs 2259 days [P < .05]). However, there was no significant change in the absolute mean delta eGFR between participants with CVE and without CVE after adjustment for age (3.8 mL/min/1.73 m2 vs 3.8 mL/min/1.73 m2 [P = .9]). Furthermore, there was no significant difference in the progression to KRT in participants with CVE compared with participants without CVE (1315 days and 1052 days (P = .46). CONCLUSION: Cardiovascular events are associated with increased mortality in the CKD cohort. They were not associated with accelerated deterioration of kidney function.

Baseline liver function tests and full blood count indices and their association with progression of chronic kidney disease and renal outcomes in Aboriginal and Torres Strait Islander people: the eGFR follow- up study.

BACKGROUND: Determination of risks for chronic kidney disease (CKD) progression could improve strategies to reduce progression to ESKD. The eGFR Study recruited a cohort of adult Aboriginal and Torres Strait Islander people (Indigenous Australians) from Northern Queensland, Northern Territory and Western Australia, aiming to address the heavy CKD burden experienced within these communities. METHODS: Using data from the eGFR study, we explored the association of baseline liver function tests (LFTs) (alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin and albumin) and full blood count (FBC) indices (white blood cell and red blood cell counts and haemoglobin) with annual eGFR decline and renal outcomes (first of 30% decline in eGFR with a follow-up eGFR < 60 mL/min/1.73 m2, initiation of renal replacement therapy, or renal death). Comparisons of baseline variables across eGFR categories were calculated using analysis of variance and logistic regression as appropriate. Linear and multivariable regression models were used to estimate the annual change in eGFR for changes in FBC indices and LFTs. Cox proportional hazard models were used to estimate the hazard ratio for developing renal outcome for changes in baseline FBC indices and LFTs. RESULTS: Of 547 participants, 540 had at least one baseline measure of LFTs and FBC indices. The mean age was 46.1 (14.7) years and 63.6% were female. The median follow-up was 3.1 (IQR 2.8-3.6) years. Annual decline in eGFR was associated with low serum albumin (p < 0.001) and haemoglobin (p = 0.007). After adjustment for age, gender, urine albumin/creatinine ratio, diabetes, BMI, CRP, WHR, alcohol consumption, cholesterol and triglycerides, low serum albumin (p < 0.001), haemoglobin (p = 0.012) and bilirubin (p = 0.011) were associated with annual decline in eGFR. Renal outcomes were inversely associated with serum albumin (p < 0.001), bilirubin (p = 0.012) and haemoglobin (p < 0.001) and directly with GGT (p = 0.007) and ALP (p < 0.001). Other FBC indices and LFTs were not associated with annual decline in eGFR or renal outcomes. CONCLUSIONS: GGT, ALP, bilirubin, albumin and haemoglobin independently associate with renal outcomes. Contrary to findings from other studies, no association was found between renal outcomes and other FBC indices. These findings may help focus strategies to prevent disease progression in this high-risk population.

The Ckd. Qld fabRy Epidemiology (aCQuiRE) study protocol: identifying the prevalence of Fabry disease amongst patients with kidney disease in Queensland, Australia.

BACKGROUND: Fabry disease (FD) is a rare, lysosomal storage disorder caused by the absence or deficiency of the enzyme alpha-galactosidase A (α-Gal A) that leads to the abnormal accumulation of the lipid globotriaosylceramide (GB3) in a variety of cell types and tissues throughout the body. FD has an x-linked inheritance pattern. Previously thought to be only carriers, females can also experience FD symptomatology. Symptoms vary in type and severity from patient to patient and tend to increase in severity with age. FD symptoms are non-specific and may be shared with those of other diseases. Misdiagnoses and diagnostic delays are common, often resulting in progressive, irreversible tissue damage. The estimated prevalence of FD in the general population is 1:40,000 to 1:117,000 individuals. However, it is estimated that the prevalence of FD in the dialysis population is 0.12 to 0.7%. Little is known about the prevalence of FD in the broader Chronic Kidney Disease (CKD) population. METHODS: This is an epidemiological study of the prevalence of FD in CKD patents identified from the public renal speciality practices in Queensland, Australia. A cascade approach to screening is being employed with dried blood spot testing for blood levels of alpha-galactosidase A (Alpha-Gal), with follow-up testing for patients with abnormal results by plasma levels of globotriaosylsphingosine (Lyso-GB3) for females and non-definitive cases in males. A diagnosis of FD is confirmed through genetic testing of the GLA gene in cases suspected of having FD based upon Alpha-Gal and Lyso-GB3 testing. DISCUSSION: Expected outcomes of this study include more information about the prevalence of FD at all stages of CKD, including for both males and females. The study may also provide information about common characteristics of FD to assist with diagnosis and optimal management/treatment. Screening is also available for family members of diagnosed patients, with potential for early diagnosis of FD and intervention for those individuals. TRIAL REGISTRATION: Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au) pj09946 (Registered 3rd July 2017).

Protocol and establishment of a Queensland renal biopsy registry in Australia.

BACKGROUND: Renal biopsy is often required to obtain information for diagnosis, management and prognosis of kidney disease that can be broadly classified into acute kidney injury (AKI) and chronic kidney disease (CKD). The most common conditions identified on renal biopsy are glomerulonephritis and tubulo-interstitial disorders. There is a paucity of information on management strategies and therapeutic outcomes in AKI and CKD patients. A renal biopsy registry will provide information on biopsy-proven kidney disorders to improve disease understanding and tracking, healthcare planning, patient care and outcomes. METHODS: A registry of patients, that includes biopsy-proven kidney disease, was established through the collaboration of nephrologists from Queensland Hospital and Health Services and pathologists from Pathology Queensland services. The registry is in keeping with directions of the Advancing Kidney Care 2026 Collaborative, established in September 2018 as a Queensland Health initiative. Phase 1 of the registry entailed retrospective acquisition of data from all adult native kidney biopsies performed in Queensland, Australia, from 2002 to 2018. Data were also linked with the existing CKD.QLD patient registry. From 2019 onwards, phase 2 of the registry involves prospective collection of all incident consenting patients referred to Queensland public hospitals and having a renal biopsy. Annual reports on patient outcomes will be generated and disseminated. DISCUSSION: Establishment of the Queensland Renal Biopsy Registry (QRBR) aims to provide a profile of patients with biopsy-proven kidney disease that will lead to better understanding of clinico-pathological association and facilitate future research. It is expected to improve patient care and outcomes.

Chronic kidney disease and socio-economic status: a cross sectional study.

Objective: This cross-sectional study investigated the relationship between individual-level markers of disadvantage, renal function and cardio-metabolic risk within an Indigenous population characterised by a heavy burden of chronic kidney disease and disadvantage.Design: Using data from 20 Indigenous communities across Australia, an aggregate socio-economic status (SES) score was created from individual-level socio-economic variables reported by participants. Logistic regression was used to assess the association of individual-level socio-economic variables and the SES score with kidney function (an estimated glomerular function rate (eGFR) cut-point of <60 ml/min/1.73 m2) as well as clinical indicators of cardio-metabolic risk.Results: The combination of lower education and unemployment was associated with poorer kidney function and higher cardio-metabolic risk factors. Regression models adjusted for age and gender showed that an eGFR < 60 ml/min/1.73 m2 was associated with a low socio-economic score (lowest vs. highest 3.24 [95% CI 1.43-6.97]), remote living (remote vs. highly to moderately accessible 3.24 [95% CI 1.28-8.23]), renting (renting vs. owning/being purchased 5.76[95% CI 1.91-17.33]), unemployment (unemployed vs employed 2.85 [95% CI 1.31-6.19]) and receiving welfare (welfare vs. salary 2.49 [95% CI 1.42-4.37]). A higher aggregate socio-economic score was inversely associated with an eGFR < 60 ml/min/1.73 m2 (0.75 [95% CI 063-0.89]).Conclusion: This study extends upon our understanding of associations between area-level markers of disadvantage and burden of end stage kidney disease amongst Indigenous populations to a detailed analysis of a range of well-characterised individual-level factors such as overall low socio-economic status, remote living, renting, unemployment and welfare. With the increasing burden of end-stage kidney disease amongst Indigenous people, the underlying socio-economic conditions and social and cultural determinants of health need to be understood at an individual as well as community-level, to develop, implement, target and sustain interventions.

Underlying Histopathology Determines Response to Oxidative Stress in Cultured Human Primary Proximal Tubular Epithelial Cells.

Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned. In this study, we investigated the phenotypic and functional response of human primary PTEC to oxidative stress, an established driver of kidney disease. Furthermore, we examined the functional contribution of the underlying histopathology of the cortical tissue used to generate our PTEC. We demonstrated that human primary PTEC from both histologically 'normal' and 'diseased' cortical tissue responded to H2O2-induced oxidative stress with significantly elevated mitochondrial superoxide levels, DNA damage, and significantly decreased proliferation. The functional response of 'normal' PTEC to oxidative stress mirrored the reported pathogenesis of human kidney disease, with significantly attenuated mitochondrial function and increased cell death. In contrast, 'diseased' PTEC were functionally resistant to oxidative stress, with maintenance of mitochondrial function and cell viability. This selective survival of 'diseased' PTEC under oxidizing conditions is reminiscent of the in vivo persistence of maladaptive PTEC following kidney injury. We are now exploring the impact that these differential PTEC responses have in the therapeutic targeting of oxidative stress pathways.

A collaborative, individual-level analysis compared longitudinal outcomes across the International Network of Chronic Kidney Disease (iNETCKD) cohorts.

Rates of chronic kidney disease (CKD) progression, end stage kidney disease (ESKD), all-cause mortality, and cardiovascular (CVD) events among individuals with CKD vary widely across countries. Well-characterized demographic, comorbidity, and laboratory markers captured for prospective cohorts may explain, in part, such differences. To investigate whether core characteristics of individuals with CKD explain differences in rates of outcomes, we conducted an individual-level analysis of eight studies that are part of iNET-CKD, an international network of CKD cohort studies. Overall, the rate of CKD progression was 40 events/1000 person-year (95% confidence interval 39 - 41), 28 (27 - 29) for ESKD, 41 (40 - 42) for death, and 29 (28 - 30) for CVD events. However, standardized rates were highly heterogeneous across studies (over 92.5%). Interactions by study group on the association between baseline characteristics and outcomes were then identified. For example, the adjusted hazard ratio for CKD progression was 0.44 (95% confidence interval 0.35 - 0.56) for women vs. men among the Japanese (CKD-JAC), while it was 0.66 (0.59 - 0.75) among the Uruguayan (NRHP). The adjusted hazard ratio for ESKD was 2.02 (95% CI 1.88 - 2.17) per 10 units lower baseline eGFR among Americans (CRIC), while it was 3.01 (2.57 - 3.53) among Canadians (CanPREDDICT) (significant interaction for comparisons across all studies). The risks of CKD progression, ESKD, death, and CVD vary across countries even after accounting for the distributions of age, sex, comorbidities, and laboratory markers. Thus, our findings support the need for a better understanding of specific factors in different populations that explain this variation.

Renal dysfunction is already evident within the first month of life in Australian Indigenous infants born preterm.

Antecedents of the high rates of chronic kidney disease in Australian Indigenous peoples may originate early in life. Fourteen percent of Australian Indigenous infants are born preterm (under 37 weeks gestation) and, therefore, at risk. Here, our observational cohort study sought to determine the impact of preterm birth on renal function in Australian Indigenous and non-Indigenous infants. Renal function was assessed between 4-29 days postnatally in 60 Indigenous and 42 non-Indigenous infants born at 24-36 weeks gestation. Indigenous ethnicity was associated with impaired renal function, with significantly higher serum creatinine (geometric mean ratio (GMR) 1.15 [1.06, 1.25]), fractional excretion of sodium (GMR 1.21 [1.04, 1.39]), and urine albumin (GMR 1.57 [1.05, 2.34]), ß-2 microglobulin (GMR 1.82 [1.11, 2.98]) and cystatin C (GMR 3.27 [1.54, 6.95]) when controlling for gestational/postnatal age, sex and birth weight Z-score. Renal injury, as indicated by high urine neutrophil gelatinase-associated lipocalin levels, was associated with maternal smoking and postnatal antibiotic exposure. Indigenous infants appeared to be most susceptible to the adverse impact of antibiotics. These findings show that preterm Australian Indigenous infants are highly vulnerable to renal dysfunction. Preterm birth may contribute to their increased risk of chronic kidney disease. Thus, we recommended that renal function should be closely monitored life-long in Indigenous children born preterm.